Suppression of peripheral NGF attenuates neuropathic pain induced by chronic constriction injury through the TAK1-MAPK/NE-κB signaling pathways

Background: Anti-nerve growth factor (NGF) monoclonal antibodies (anti-NGF mAbs) have been reported to significantly attenuate pain, but the mechanism involved has not been fully elucidated, and the serious adverse events associated with mAbs seriously limit their clinical use. This study further investigated the mechanism by which peripheral NGF is involved in neuropathic pain and found safe, natural compounds that target NGF to attenuate neuropathic pain. Methods: Nociception was assessed by the Von Frey hair and Hargreaves' methods. Western-blotting, qPCR and immunofluorescence were used to detect the cell signaling pathway. RAW264.7 macrophages and RSC96 Schwann cells were cultured for in vitro evaluation. Results: Intraplantar administration of anti-NGF mAbs suppressed the expression of phosphorylated transforming growth factor-beta-activated kinase 1 (TAK1) in the dorsal root ganglion (DRG) and sciatic nerve. Intraplantar administration of a TAK1 inhibitor attenuated CO-induced neuropathic pain and suppressed the expression of phosphorylated mitogen-activated protein kinases (MAPKs) in the DRG and sciatic nerve. Perisciatic nerve administration of levo-corydalmine (/-CDL) on the operated side obviously attenuated CO-induced neuropathic pain and suppressed the expression of mNGF and proNGF. In addition, /-CDL-induced antinociception was reversed by intraplantar administration of NGF. Further results indicated that I-CDL-induced suppression of phosphorylated TAK1, MAPKs, and p65 and expression of the proinflammatory cytokines TNF-alpha and IL-1 beta in the DRG and sciatic nerve were all abolished by NGF. In addition, in vitro experiments indicated that /-CDL suppressed the secretion of NGF and proNGF in RAW264.7 macrophages and RSC96 Schwann cells, which was abolished by AP-1 and CREB agonists, respectively. Conclusions: This study showed NGF inhibition suppressed TAK1 in the periphery to attenuate CCI-induced neuropathic pain through inhibition of downstream MAPK and p65 signaling. The natural compound /-CDL inhibited NGF secretion by macrophages and Schwann cells and downstream TAK1-MAPK/NF-kappa B signaling in the periphery to attenuate CCI-induced neuropathic pain.